Mitochondrial DNA Damage and Brain Aging in Human Immunodeficiency Virus. (28th July 2020)

• Record Type: Journal Article
• Authors: Roca-Bayerri, Carla; Robertson, Fiona; Pyle, Angela; Hudson, Gavin; Payne, Brendan A I
• Is Part Of: Clinical infectious diseases. Volume 73:Number 2(2021)
• Page Start: e466
• Page End: e473
• Publication Date: 2020-07-28
• Subjects: mitochondrial DNA -- HIV -- antiretroviral therapy -- HIV-associated neurocognitive disorders -- aging; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciaa984
• Languages: English
• ISSNs: 1058-4838

Abstract

Abstract: Background: Neurocognitive impairment (NCI) remains common in people living with human immunodeficiency virus (PLWH), despite suppressive antiretroviral therapy (ART), but the reasons remain incompletely understood. Mitochondrial dysfunction is a hallmark of aging and of neurodegenerative diseases. We hypothesized that human immunodeficiency virus (HIV) or ART may lead to mitochondrial abnormalities in the brain, thus contributing to NCI. Methods: We studied postmortem frozen brain samples from 52 PLWH and 40 HIV-negative controls. Cellular mitochondrial DNA (mtDNA) content and levels of large-scale mtDNA deletions were measured by real-time polymerase chain reaction. Heteroplasmic mtDNA point mutations were quantified by deep sequencing (Illumina). Neurocognitive data were taken within 48 months antemortem. Results: We observed a decrease in mtDNA content, an increase in the mtDNA "common deletion, " and an increase in mtDNA point mutations with age (all P < .05). Each of these changes was exacerbated in HIV-positive cases compared with HIV-negative controls (all P < .05). ART exposures, including nucleoside analogue reverse transcriptase inhibitors, were not associated with changes in mtDNA. The number of mtDNA point mutations was associated with low CD4/CD8 ratio ( P = .04) and with NCI (global T-score, P = .007). Conclusions: In people with predominantly advanced HIV infection, there is exacerbation of age-associated mtDNA damage. This change is driven by HIV per se rather than by ART toxicity and may contribute to NCI. These data suggest that mitochondrial dysfunction may be a mediator of adverse aging phenotypes in PLWH. Abstract : Brain tissue from people living with HIV shows depletion of mitochondrial DNA (mtDNA) content and an increase in mtDNA mutations. These changes augment those seen with normal aging and may contribute to cognitive impairment.